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The feasibility of a randomized controlled trial of esophagectomy for esophageal cancer - the ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open) study: protocol for a randomized controlled trial

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Abstract

Background

There is a need for evidence of the clinical effectiveness of minimally invasive surgery
for the treatment of esophageal cancer, but randomized controlled trials in surgery
are often difficult to conduct. The ROMIO (Randomized Open or Minimally Invasive Oesophagectomy)
study will establish the feasibility of a main trial which will examine the clinical
and cost-effectiveness of minimally invasive and open surgical procedures for the
treatment of esophageal cancer.

Methods/Design

A pilot randomized controlled trial (RCT), in two centers (University Hospitals Bristol
NHS Foundation Trust and Plymouth Hospitals NHS Trust) will examine numbers of incident
and eligible patients who consent to participate in the ROMIO study. Interventions
will include esophagectomy by: (1) open gastric mobilization and right thoracotomy,
(2) laparoscopic gastric mobilization and right thoracotomy, and (3) totally minimally
invasive surgery (in the Bristol center only). The primary outcomes of the feasibility
study will be measures of recruitment, successful development of methods to monitor
quality of surgery and fidelity to a surgical protocol, and development of a core
outcome set to evaluate esophageal cancer surgery. The study will test patient-reported
outcomes measures to assess recovery, methods to blind participants, assessments of
surgical morbidity, and methods to capture cost and resource use. ROMIO will integrate
methods to monitor and improve recruitment using audio recordings of consultations
between recruiting surgeons, nurses, and patients to provide feedback for recruiting
staff.

Discussion

The ROMIO study aims to establish efficient methods to undertake a main trial of minimally
invasive surgery versus open surgery for esophageal cancer.

Keywords:

Background

Esophageal cancer is the ninth most common cancer in the United Kingdom (UK), and
around 8,000 people are newly diagnosed with the disease each year [1]. Surgery alone or in combination with chemotherapy or chemoradiation treatment is
the mainstay of cure for localised esophageal adenocarcinoma and one of several options
for esophageal squamous cell cancer, which may also be radically treated with definitive
chemoradiotherapy or radiotherapy alone. Esophagectomy for esophageal cancer is a
major procedure. Audit data for 1220 esophagectomies carried out in England and Wales
from April 2011 to March 2012 showed that 29.7% of patients would experience a complication
while 8.9% would experience serious morbidity requiring a re-operation [2]. The thirty-day mortality rate is 1.7% [2]. Esophagectomy also has a major short-term detrimental impact on health-related quality
of life (HRQL), with patients reporting a reduction in physical and social function
and marked increases in fatigue, breathlessness, and pain scores for at least three
months after surgery [3,4] and persistent long-term deficits can occur [3]. These morbidities need to be considered alongside the evidence that esophagectomy
offers long-term survival in the region of 20 to 40% [5-7].

There are several approaches for the resection of esophageal tumors. Surgery may involve
two or three phase procedures (abdominal, chest and/or neck incisions) or a transhiatal
approach (abdominal and cervical incision); each of these may be performed with minimal
access or open approaches. The past decade has seen a growing interest in minimal
access surgical techniques for all types of cancer surgery, with the potential advantages
of causing less tissue trauma and better recovery. In England and Wales, 43% (492
out of 1140) of esophagectomies performed during the period of the recent national
audit used minimal access surgical techniques [2]. These were mostly (321 out of 492, 65%) laparoscopically assisted two-phase approaches
(minimal access approach for the abdomen and standard open right chest incision),
with the others being totally minimally invasive esophagectomy (MIO). The audit data
suggested that length of hospital stay and inpatient complication rates following
open and minimal access approaches were similar, with the small differences observed
being consistent with chance. The biggest difference was in respiratory complications,
the rate of which was observed to be lower in MIO (11%, 18 out of 171 assuming no
missing data) than in open procedures (17%, 108 out of 647), a difference which is
unlikely to occur by chance (P = 0.047, chi-square test), but the interpretation of this finding is complicated
by the highest rate of respiratory complications occurring following the hybrid procedures
(22% 70 out of 321). This is one example of the complex data that can result from
observational studies, where the different procedures may be undertaken by surgeons
with different levels of experience and in patients selected for particular interventions
with different baseline prognostic factor (for example age, fitness, and tumor stage)
profiles.

Whilst a number of systematic reviews have been conducted, these all focus on data
from observational studies [8-17]. Such studies are subject to the same caveats as stated above, and whilst they suggest
that minimally invasive techniques may improve short-term clinical outcomes (such
as morbidity and physiological measures) [18] and reduce impact on HRQL during recovery [19], these results must be interpreted with caution. Furthermore, even these weak studies
tell us little about long-term survival [20], cost effectiveness, and impact on long-term HRQL [8,21].

There are a limited number of small randomized trials, including the recently reported
Dutch TIME trial (Traditional invasive versus minimally invasive esophagectomy), which
compared open two or three phase esophagectomy (56 patients) with totally MIO (59
patients) and reported short-term outcome data [22]. The trial provided evidence that minimally invasive esophagectomy was associated
with a lower incidence of in-hospital pulmonary infection (12% versus 34%) and a shorter
hospital stay (median 11 days versus 14 days) compared to open surgery. The trial
report was followed by a critical correspondence from the surgical community [23-26], much of which reflected a failure to appreciate the pragmatic approach necessary
to evaluate complex interventions [27]. At the time of writing, the French MIRO (oesophagectoMIe pour cancer paR voie conventionnelle
ou coeliO-assistée) trial is in progress, randomly allocating 200 patients between
open and laparoscopically-assisted esophagectomy. Again the focus will be on short-term
complications (major morbidity within 30 postoperative days) [28]. Whilst both the TIME and MIRO trial contribute important data, there is a need for
a larger multicenter trial that is designed to assess the longer-term clinical effectiveness
of minimally invasive surgery. This trial needs to have a sufficient sample size to
demonstrate that any advantages of the minimally invasive procedure for recovery and
longer-term HRQL are achieved without compromising the survival benefits of surgical
intervention.

There are a number of challenges to conducting randomized controlled trial (RCT) evaluations
of novel interventions which need highly skilled operators, and further problems to
overcome in evaluations of surgery in particular [29]. These include the anxiety patients may have with leaving a decision between what
can be quite different interventions to chance, ensuring a fair comparison between
novel and standard techniques when surgeons are refining their skills in the former
as the trial progresses, and keeping the patient and other assessors of outcome blind
to individual treatment allocations, at least for the initial assessments of recovery.
There is no doubt that patients undergoing esophagectomy are subject to a ‘complex
intervention’, commonly defined as an intervention comprising multiple interacting
aspects [30]. It is increasingly accepted that evaluations of such complex interventions should
be preceded by feasibility work to establish if a main trial can recruit sufficient
participants within an acceptable time, to standardize the interventions and establish
criteria for their adequate implementation, and to establish the most appropriate
measures of outcome for the main trial.

This protocol paper describes the ROMIO (Randomized Oesophagectomy: Minimally Invasive
or Open) study in which we aim to standardize minimally invasive procedures for esophagectomy
in order to refine our approach to evaluating MIO compared to open procedures in a
RCT, and to determine the feasibility of a multicenter trial comparing the clinical
and cost-effectiveness of minimally invasive and open surgical procedures in patients
with cancer of the esophagus. The specific objectives of the ROMIO feasibility study
are listed below.

List of ROMIO feasibility study objectives

(ii) establish the proportion of patients who are potentially eligible and successfully
recruited to inform sample size calculations for the main trial;

(iii) document in detail, using IDEAL recommendations[31], the technical developments of totally MIO to inform the design and choice of interventions
in the main trial;

(iv) develop a manual for optimizing pathology procedures and reporting, including
lymph node counts and ascertainment of positive resection margins, which are likely
to be short-term outcome measures for the main trial;

(vi) develop and evaluate feasible, acceptable, and effective methods of blinding
patients for the first week postoperatively, so reducing bias in self-reported outcomes;
and

(vii) establish outcome measures for the main trial that enable a comprehensive, valid,
and reliable assessment of esophagectomy outcome, and which include a set of core
outcome measures considered to be essential in clinical effectiveness RCTs of esophageal
cancer surgery.

Methods/Design

ROMIO is a two-year external feasibility study with a pilot parallel group RCT at
its core. The pilot trial is recruiting at two UK centers: University Hospitals Bristol
NHS Foundation Trust and Plymouth Hospitals NHS Trust. Both centers have a team of
upper gastrointestinal cancer surgeons (six in Bristol and five in Plymouth) and each
undertake 50 to 100 resections for esophago-gastric cancer per year.

Participants

All referrals of patients with esophageal cancer or high-grade dysplasia requiring
surgery for primary esophagectomy or neoadjuvant chemotherapy before esophagectomy
at the Bristol and Plymouth centers are considered for eligibility. Patients recommended
for neoadjuvant chemotherapy and surgery are registered in the screening log but full
eligibility is only confirmed once chemotherapy is completed, restaging undertaken,
and the multidisciplinary team (MDT) of clinicians confirms that they will proceed
to surgery. At this point eligible patients are informed about the trial and invited
to have the method of their esophagectomy randomly selected from between open gastric
mobilization and right thoracotomy, laparoscopic gastric mobilization and right thoracotomy,
or (Bristol center only) totally minimally invasive surgery (Figure 1).

Inclusion criteria

Participants may enter the study if ALL of the following apply: (1) male or female
patients, (2) over 18 years of age, (3) referred by the MDT for primary esophagectomy
or esophagectomy following restaging after neoadjuvant chemotherapy (of any type including
chemoradiotherapy), (4) confirmed histopathological evidence of esophageal or esophago-gastric
junctional adenocarcinoma, squamous cell cancer, or high-grade dysplasia, (5) fit
for preoperative anaesthesia and surgery, assessed by the MDT, (6) able to provide
written informed consent, (7) endoscopic measurement before chemotherapy that the
tumor starts more than 5 cm below the crico-pharyngeus, (8) endoscopic measurement
before chemotherapy that the tumor involves less than 4 cm of the gastric wall, and
(9) the final pretreatment tumor stage is between high-grade dysplasia and T4aN1M0.

Exclusion criteria

Participants may not enter the study if any of the following apply: (1) stage 4 disease,
(2) type three tumors of the esophago-gastric junction that are scheduled for total
gastrectomy, (3) patients with squamous cell cancer of the esophagus who the MDT recommends
for, or who individually elect to undergo, definitive chemoradiotherapy, (4) evidence
of previous complex thoracotomies or laparotomies, (5) evidence of previous or concomitant
malignancy that would interfere with this treatment protocol, (6) pregnancy, (7) patients
participating in other trials that would interfere with the implementation of this
protocol at a particular study center.

Randomization

Internet-accessed randomization is conducted centrally at the Bristol Randomized Trials
Collaboration (BRTC), a UK Clinical Research Collaboration registered Clinical Trials
Unit hosted by the University of Bristol. Randomization within blocks of varying size
is conducted separately for the two centers and further stratified by whether the
patient has undergone neoadjuvant treatment or not. In Bristol, patients are randomly
allocated in a 1:1:1 ratio to one of three arms: open esophagectomy (open gastric
mobilization and right thoracotomy), laparoscopic-assisted esophagectomy (laparoscopic
gastric mobilization and right thoracotomy) or totally minimally invasive surgery.
In Plymouth, randomization is restricted to two of the study arms, open esophagectomy
or laparoscopic-assisted esophagectomy (Figure 1), in a 1:1 ratio. Patients must be logged into the trial and issued with a unique
study ID number prior to the treatment allocation being generated, so ensuring judgments
about eligibility are made without knowledge of what the next allocation will be (allocation
concealment).

Trial interventions

During the trial the surgical procedures are carried out under general anaesthesia
with all patients receiving antibiotic and deep vein thrombosis (DVT) prophylaxis
according to local hospital policies. The surgical procedures last between 5 and 8 hours.
For the purposes of this pragmatic trial each intervention is allowed to be implemented
according to the standard local policy, so long as there is consistency with the aspects
of each intervention the study team currently consider as mandatory or prohibited
for the particular method, as described below. This approach will be formalized in
a process evaluation during this feasibility study leading to the production of an
intervention manual and an assessment of the adequate standard of, and fidelity to,
each procedure undertaken. The process evaluation will consider the surgical intervention
itself and concomitant interventions.

Open esophagectomy

In the ROMIO feasibility study the operation consists of a two-phase esophagectomy
(abdomen and right chest) with a two-field lymphadenectomy (abdomen and thorax) and
involves two key steps or phases.

Abdominal phase

The incision (midline or subcostal) is at the surgeon’s discretion. Complete gastric
mobilization will be performed based on the right gastroepiploic and right gastric
arteries. Pyloroplasty, pyloromyotomy, or no drainage is at the surgeon’s discretion.
Lymphadenectomies are performed along the common hepatic artery and the left gastric
and splenic artery either en bloc or separately, and removal of sufficient crural fibres and a cuff of diaphragm performed
if required for tumor clearance. The pericardial fat pad and strips of pleura are
removed. Transection of the lesser curve may be undertaken or left to the thoracic
phase of the operation. Placement of a feeding jejunostomy or naso-jejunal tube is
at the surgeon’s discretion as are placement of intra-abdominal and intra-thoracic
drains. Methods to close the abdomen are at the surgeon’s discretion.

Thoracic phase

The chest is opened through a right thoracotomy and the mediastinal pleura overlying
the esophagus excised in continuity with the esophagus. The posterior limit of the
dissection should be the antero-lateral wall of the aorta. The thoracic duct is mobilized
en bloc or separately to the esophagus and periesophageal tissues. The thoracic duct is ligated
and divided at the level of the diaphragm. The esophagus is mobilized to the level
of at least the aortic arch or higher if required. The para-esophageal and diaphragmatic
nodes are removed in continuity with the esophagus. The lymph nodes at the tracheal
bifurcation and along the right and left main bronchi to the pulmonary hilus can be
removed en bloc or separately at the surgeon’s discretion. The anastomotic technique and method of
chest drainage is at the surgeon’s discretion. Methods to close the chest are at the
surgeon’s discretion.

Laparoscopically assisted esophagectomy

This operation consists of identical steps as described for the open esophagectomy,
but access to the abdominal cavity is achieved with four or five 10 or 5 mm incisions
and surgery performed laparoscopically. Placement of a feeding jejunostomy is at the
surgeon’s discretion and may be performed laparoscopically or by extending a port
site to an 8 cm abdominal incision. The thoracic part of the operation is performed
as described for the open esophagectomy.

Totally minimally invasive esophagectomy

This consists of performing the steps of the abdominal and chest phases of the operation
as described for the open esophagectomy. These are performed with abdominal and chest
ports positioned by the surgeon at their discretion. Within the ROMIO feasibility
study it is also possible to perform a three phase procedure (undertaking the anastomosis
with a left cervical incision). Surgeons in Bristol undertaking the totally minimally
invasive procedure are recording variations to this outlined approach, with reasons,
during this feasibility study to inform the design and interventions to be evaluated
in the main trial.

Concomitant interventions and the enhanced recovery protocol

Concomitant interventions are defined as naturally accompanying or associated elements
of the surgical intervention itself, and can be divided into preoperative, perioperative
and postoperative components. Concomitant interventions to be considered as part of
the process evaluation during the pilot trial include the anaesthetic and other perioperative
procedures, immediate postoperative care (including intensive care management), and
patient rehabilitation, input from allied health professionals such as physiotherapists
and dieticians, which may or may not be encompassed into a formal enhanced recovery
program. During the ROMIO feasibility study standard protocols for follow-up care
after both procedures will be developed to minimize the risk of performance bias arising
from carers differentially providing co-interventions in the main trial.

This work will inform development of an enhanced recovery pathway or manual to be
used in the main trial to provide the minimum standard of care permitted. Together
with the surgical intervention itself, concomitant interventions will be considered
during the process evaluation and incorporated into the manual if identified as important.

Outcome measures

The primary outcome for the main trial is currently planned to be patient-reported
physical fatigue, as measured by the Multidimensional Fatigue Inventory MFI-20 [32,33] measuring fatigue at several time points during the first three months post-surgery;
the speed of recovery of each patient will be captured.

During the pilot trial we are asking participants to complete a range of measures
which are being considered as secondary outcome measures for the main trial [34-36]. These are listed below. In addition, post-surgery morbidity will be classified according
to both the Accordian and Clavien-Dindo schemes [37,38].

List of pilot trial secondary outcome measures

Date and cause of death

Disease recurrence with date

Lung function

Patient completed visual analogue scale assessment of pain

Patient completed questionnaires on generic HRQL: EuroQoL EQ-5D-5 L

Patient completed questionnaires on disease-specific HRQL: European Organisation for
Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)
and the esophageal specific module (QLQ-OES18)

Development of a core clinical outcome set for esophageal cancer surgery

The ROMIO feasibility study provides the opportunity to develop a core outcome set
for esophageal cancer surgery [39,40]. A core outcome set is a standardized set of clinical outcomes that represents the
minimum that should be measured and reported in all clinical trials [40]. A relatively long list of potential outcomes will be generated by surveying patients
and clinicians, which will be reduced to those considered crucial and distinctive
through a Delphi exercise. This work will link with 'COMET' (Core Outcome Measures
in Effectiveness Trials), funded by the Medical Research Council ConDuCT (Collaboration
and innovation in difficult randomized controlled trials) Hub for Trials Methodology
Research and North West Hubs for trials methodology research [40]. The final core set of outcomes for esophageal cancer surgery is expected to be less
than 10 items.

Development of resource use data collection

During the ROMIO study best methods for capturing cost and resource use in relation
to the interventions and follow-up in secondary care are being established. Questionnaires
are also being developed in order to collect information about the use of primary
NHS services and social services and direct and indirect costs incurred by patient
and carers. The average costs for all the different categories will be compared by
study arm to enable the main cost drivers of the interventions to be established and
compared. Any areas where obtaining accurate estimates of costs is problematic will
also be identified. This will allow a more focused collection of resource use data
and a more accurate estimate of cost-effectiveness in the main trial.

Data collection

Socioeconomic details and height are measured when the patient is seen for a pre-surgery
assessment only. Lung function measurements and assessments of pain are taken pre-surgery,
during the first week post-surgery, and at days three and six as a minimum. HRQL is
assessed using standardized questionnaires pre-surgery and at 6, 42, 90, and 185 days;
questionnaires are posted with a stamped addressed envelope when necessary. Resource
use is assessed through medical records review and interviews with patients.

Through medical records review, routine clinical measures are also captured whenever
they are taken as part of the patient’s care during the six month study period. Clinical
report forms designed for the study are used to formalize this data collection. Measures
of the surgical process (for example blood loss or duration of surgery) and pathological
assessment of the tumor and lymph nodes are included in this collection.

Sample size calculation and statistical analysis

In the feasibility study recruitment is occurring initially over a 12-month period,
with 72 potentially eligible patients expected during that time. This will allow a
true 50% recruitment rate to be estimated with a 95% confidence interval of approximately
38 to 62%. If 11 patients are randomly allocated to each surgical procedure this will
allow a true difference of 1.25 standard deviations between two procedures on a continuous
measure of early outcome to be detected with 80% power at the 5% significance level.
Hence the pilot trial will provide an acceptably precise estimate of the recruitment
rate to inform plans for the main trial, and may provide evidence suggesting that
a particular method may be achieving relatively poorer short-term outcomes and may
need to be refined before proceeding to the main study.

Summary statistics that will inform plans for the main trial will be presented, including
(in a CONSORT chart format) the number of potentially eligible and confirmed patients
per month per center and the percentage of patients agreeing to randomization and
completing outcome measurements. Mean scores on short-term outcome measures will be
presented for each study arm, with P values and 95% confidence intervals presented for treatment comparisons where at
least 10 patients have been randomized to each study arm. No conclusions about the
relative clinical effectiveness of the three interventions will be drawn from these
results; they will purely inform the refinement of the interventions prior to proceeding
to the main trial. Additional summary statistics will arise from the pilot work, for
example, mean scores on the blinding scale achieved by different blinding procedures.

Quality control of surgery and development of the surgical manual

Only surgeons or trainees under direct supervision perform the procedures. A sample
of procedures is being video recorded for analysis by the research team at Imperial
College London. This will inform the development of the following resources for the
main trial: (1) a surgical manual to define the framework for the steps of each trial
intervention and describe acceptable and prohibited (unacceptable) protocol deviations;
(2) an esophageal competency-assessment tool (O-CAT) based on the Observational Clinical
Human Reliability Assessment (OCHRA) techniques to assess the level of competency
for technical surgical performance [41], including adherence to procedural steps, protocol deviations, errors, and near miss
events; and (3) a manual to describe details of concomitant interventions, such as
type of anaesthesia, pre- and postoperative rehabilitation, and key elements of enhanced
recovery pathways which are important in fulfilling the CONSORT criteria for reporting
evaluations of complex interventions [30].

Pathological specimens are processed in an agreed uniform manner in both centers and
dissection of lymph nodes from the main specimen and lymphadenectomy specimens follow
a pro forma. These processes are reviewed regularly in both centers and standardized
techniques for sampling lymph nodes are adopted so that the maximum yield can be obtained
from all cases. Involvement of the surgical resection margin is assessed both microscopically
and macroscopically.

Blinding patients

Methods to achieve blinding of patients and outcome assessors to the type of surgery
during the initial post-surgery period are being piloted. In the first seven days
post-surgery patients are blinded by using large adhesive dressings that are positioned
similarly on all trial patients regardless of the type of surgery (covering the abdominal,
thoracic, and cervical incisions). Patients are asked to turn their head away during
dressing changes and on days two and six they are asked to complete the Bang Blinding
Index, which assesses blinding success by asking patients to guess their arm allocation
[42]. The Bang Blinding Index is administered by ward or nursing staff not routinely involved
in the patient’s care. Patients’ experiences of blinding and experiences of ward staff
and nurses involved with these processes are being further explored in qualitative
interviews described below.

Recruitment investigation

The ROMIO trial compares different surgical procedures that are in common use in specialist
centers, and therefore the trial is likely to face a number of recruitment challenges.
Based on previous works by de Salis et al. and Donovan et al.[43-49], a key component of the pilot trial is an integrated qualitative study which is exploring
these challenges to inform the design of the main ROMIO trial. Interviews with members
of the trial management group, principal investigators and active recruiters explore
their own views about the trial including their knowledge of the evidence and equipoise,
and any recruitment challenges expected or experienced. The patient pathway is mapped
through recruitment and appointments are audio recorded to scrutinize information
provision and identify issues potentially affecting trial recruitment along that pathway.
This will inform the development of information and training programs for the main
trial. Finally, interviews with a sample of eligible patients will explore patient
perspectives of surgery, previous experiences with treatments, views about surgery,
and the acceptability of randomization between the procedures.

Emerging issues related to trial design and conduct that may be hindering recruitment
are discussed between the trial team and a plan to improve recruitment during the
pilot trial will be introduced if necessary. This may include reconsideration of eligibility
criteria, study information, advice about presenting the study, discussions about
equipoise or evidence, issues with patient pathways, and logistical issues in particular
centers. These may be addressed by changes to study information or the protocol, or
training for recruiters.

Ethical approval and informed consent

Ethical approval was granted by the South West - Frenchay Research Ethics Committee
(12/SW/0161). Informed consent is obtained from each participant in the ROMIO study.

Discussion

Currently, there is a lack of published data from RCTs to support the patient benefit
of minimally invasive surgery for esophageal cancer. The well-known challenges with
conducting surgical trials need to be overcome to ensure that a multicenter pragmatic
trial can be carried out efficiently. The ROMIO pilot trial has been designed as a
necessary precursor to a main trial, during which the methodology and infrastructure
for a trial will be established.

To have impact on clinical practice we anticipate that the main study will need to
demonstrate more rapid recovery following MIO and the hybrid procedure compared to
open esophagectomy, whilst showing that the same survival benefits are achieved. In
the following illustrative calculations it is assumed that the between-center variation
in outcome is accommodated by an intra cluster correlation of 0.1, and that each center
will recruit 40 participants [50]. With the anticipated primary outcome measure of fatigue, the MFI-20 [32,33], 425 patients in each group would allow a difference of one half of a standard deviation
to be demonstrated when comparing two treatment groups, with 90% power at the 5% significance
level. Based on a one-sided 95% confidence interval, this sample size would also allow
an absolute mortality risk difference at 12 months of 15% or more to be ruled out,
with 80% power, when comparing the minimally invasive (22.5% mortality) to the open
procedure (7.5% mortality).

The ROMIO pilot study has been designed to allow centers to opt to recruit into a
two or a three arm study. Where the three arm trial has been performed, the technique
for totally minimally invasive surgery has been deliberately allowed to evolve during
the pilot study to document the technical changes and outcomes. Whether a totally
minimally invasive approach can be used in many centers in the main trial is uncertain
because it is not widely practiced in the UK. The final design of the main trial,
therefore, will be considered by the trial oversight steering group in discussion
with the trial management group and be selected to reflect current UK practice and
emerging evidence.

Trial status

The ROMIO feasibility trial recruited and randomized the first patient in April 2013.
Recruitment is above the expected target and the feasibility work will be completed
on schedule. The main trial is under design at present.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

KA drafted the manuscript based on the trial proposal and protocol, reviewed the protocol
and developed the qualitative aspects. CPB designed the trial proposal and provided
surgical expertise. RB designed the trial proposal and provided surgical expertise.
JB drafted the manuscript based on the trial proposal and protocol, designed the trial
proposal, provided surgical expertise, developed aspects of the protocol related to
quality assurance of surgery and developed health economics aspects of the protocol.
JD designed the trial proposal and developed qualitative aspects of the protocol.
JE reviewed the protocol and contributed to aspects related to patient and public
involvement. SF provided oncological expertise and reviewed the trial proposal. RG
developed pathology aspects of the protocol. GH developed aspects of the protocol
related to developing the manual and quality assurance of surgery. AH provided surgical
expertise and designed the trial protocol. RK provided surgical expertise and reviewed
the trial protocol. CM drafted the manuscript based on the trial proposal and protocol,
designed the trial proposal and developed the statistical aspects of the protocol.
SN developed health economics aspects of the protocol. CS provided surgical expertise
and reviewed the trial protocol. GS provided surgical expertise and reviewed the trial
protocol. DT provided surgical expertise and reviewed the trial protocol. TW provided
surgical expertise and designed the trial protocol. All authors read and approved
the final manuscript.

The ROMIO study is funded by the National Institute for Health Research (NIHR) Health
Technology Assessment (HTA) Programme (HTA 10/50/65). This report is independent research
commissioned by the National Institute for Health Research (HTA programme, 10/50/65
– The ROMIO trial. Randomised Oesophagectomy: Minimally Invasive or Open, a feasibility
study). The views expressed in this publication are those of the authors and not necessarily
those of the NHS, the National Institute for Health Research or the Department of
Health. Recruitment figures are submitted to the funders on a monthly basis and a
full progress report is submitted every six months. As a feasibility study, ROMIO
was permitted by its funders to have a combined Trial Steering Committee and Data
Monitoring Committee; this committee is chaired by Professor Craig Ramsay, University
of Aberdeen. The ROMIO study team acknowledges the support of the National Institute
for Health Research, through the West of England Clinical Research Network.